Iron deficiency (ID) affects an estimated 2 billion people, especially pregnant women and their infants. ID is harmful to early-life brain development and causes learning and memory deficits in children. More troubling from a public health perspective is that the learning and memory impairments persist into adulthood in both untreated as well as treated populations. Persistence of brain impairment following iron treatment in infancy implies that iron therapy alone is not sufficient for full recovery or that iron therapy itself may be harmful. These long-term effects of early-life ID are the real cost to society because of lost education and job potential. The fetal/neonatal brain is highly metabolic, accounting for 60% of total body oxygen consumption. The hippocampus has one of the highest regional metabolic rates in the neonatal brain. Iron provides the catalytic component for enzymes required for electron transport and energy production. In mice, early-life hippocampal neuronal ID reduces neuronal energy metabolism including oxidative phosphorylation and glycolysis, slows mitochondrial recruitment to active sites of growing dendrites/spines, increases reactive oxygen species (ROS) and truncates dendrite and synapse development. These findings persist into adulthood despite iron repletion. The cellular mechanisms of how developmental ID causes long-term neuronal structural deficits and whether these can be prevented or treated are unclear. We will test the overall hypothesis that early-life reprogramming of hippocampal energy metabolism, which is a potentially adaptive response to fetal/neonatal ID, becomes maladaptive in the long-term and results in structural abnormalities in the formerly ID adult hippocampus. In Aim 1, we will utilize a unique in vitro model of chronic neonatal hippocampal neuronal ID to test therapies that address fundamental energy processes disrupted by ID during development in order to prevent neuronal structural deficits. To do this, we will genetically, nutritionally or pharmacologically manipulate specific metabolic functions in iron-sufficient and -deficient neonatal hippocampal neuron cultures. Mitochondrial oxygen consumption rate and cellular glycolytic rate, mitochondrial recruitment to active sites of growing dendrites/spines and ROS will be measured in response to the manipulations. Resultant dendrite complexity and spine density/morphology will be assessed as outcome measures. Aim 2 translates Aim 1's in vitro findings to an in vivo mouse model to test which therapies delivered to the neonatal mouse prevent permanent abnormalities in mitochondrial function, dendrite structure and neurocognitive behavior in adulthood. Our unique non-anemic, hippocampal neuron-specific dominant/negative TfR-1 mouse model provides the perfect platform to assess the translational effects. This proposal is highly significant because it defines for the first time how the specific deficits in neuronal energy metabolism induced by early-life ID independent of anemia lead to long-term abnormalities in mitochondrial metabolism and neurological deficits. It tests mechanistically and empirically derived therapies to prevent them.